Injection formulations of avermectins and milbemycins based on castor oil

ABSTRACT

Injection formulations of avermectins and milbemycins based on castor oil are disclosed.

The invention relates to new injection formulations of avermectins andmilbemycins in animals, based on castor oil.

Injection formulations of ivermectin are disclosed in EP-A 146 414. Theformulations contain a solvent mixture of propylene glycol and glycerolformal in the ratio 60:40 v/v. It is known of propylene glycol that incertain concentrations it can cause local intolerabilities (see review:B. Kruss, Acta Pharm. Technol. 35(4) (1989) 187-196). The precipitationof the water-insoluble active compound ivermectin can also occur in thetissue around the administration site. Thus when using correspondingformulations marked swellings and tissue incompatibilities were observedat the injection sites, some of which only receded after several weeks.

Injection formulations of specific avermectins are disclosed in EP-A 393890. They are oil formulations based on sesame oil and ethyl oleate inthe ratio 90:10 v/v. These formulations are tolerable, but have thedisadvantage that on storage in a refrigerator at 4° C. a flocculentprecipitate is formed even after a few days.

Further injection formulations of avermectins are disclosed in EP-A 45655. The formulations described there contain comparatively high amountsof emulsifiers and in some cases are not very tolerable.

Injection formulations of avermnectins which contain triacetin (glyceroltriacetate) are described in EP-A 413 538. In EP-A 535 734, injectionformulations of avermectins based on triacetin and hydrogenated castoroil are described.

Further formulations for the injection of milbemycins and avermectinsare described in EP-A 525 307. The formulations are prepared by fusingglycerol tristearate with the active compound and mixing with an oilyneutral triglyceride and emulsifying using, for example, methylcelluloseand salts. The average particle size in the microemulsion thus obtainedshould be between 25 and 300 μm.

The present invention relates to injection formulations of avermectinsand milbemycins based on castor oil.

The formulations preferably contain

1. active compound 0.1 to 10% by weight

2. castor oil 15 to 50% by weight

3. One or more co-solvents from the series consisting of vegetable orsynthetic fatty acid esters of mono- or polyhydric alcohols, aliphaticor aromatic alcohols, cyclic carbonates in concentrations of 30 to 85%by weight

4. if appropriate, further auxiliaries.

The formulations according to the invention have an outstandingsolubility for the active compounds.

The high viscosity of castor oil can be adjusted to a desired lowervalue by addition of medium-chain triglycerides or propylene glycoloctanoate/decanoate or ethyl oleate. Additionally, the solubility of theactive compound can be improved, the viscosity further reduced and thebioavailability of the active compound improved by addition ofrelatively small volumes of hydrophilic solvents such as benzyl alcohol,propylene glycol or propylene carbonate with retention of a single-phasesystem. The new formulations are extremely highly tolerable and have ahigh bioavailability.

The active compounds employed in the formulations according to theinvention are known.

Avermectins were isolated from the microorganism Streptomycesavermitilis as microbial metabolites (U.S. Pat. No. 4,310,519) and canoccur essentially as a mixture consisting of the eight componentsA_(1a), A_(1b), A_(2a), A_(2b), B_(1a), B_(1b), B_(2a), and B_(2b) (I.Putter et al., Experentia 37 (1981) p. 963, Birkhauser Verlag(Switzerland)). In addition, the synthetic derivatives, in particular22,23-dihydroavermectin B₁ (ivermectin), are also of interest (U.S. Pat.No. 4,199,569). Milbemycin B-41 D was isolated from Streptomyceshygroscopicus by fermentation (cf. "Milbemycin: Discovery andDevelopment", I. Junya et al., Annu. Rep. Sankyo Res. Lab. 45 (1993),pp.1-98; JP Pat. 8,378,549; GB 1,390,336).

The use of the avermectins, e.g. 22,23-dihydroavermectins B₁,(ivermectin) and milbemycins as endoparasiticides is known and is thesubject of numerous patent applications and review articles (e.g.biological actions in: "Ivermectin and Abamectin", W. C. Campbell, Ed.,Springer Verlag, New York, N.Y., 1989; "Avermectins and Milbemycins PartII" H. G. Davies et al., Chem. Soc. Rev. 20 (1991) pp. 271-339; chemicalmodifications in: G. Lukacs et al. (Eds.), Springer Verlag, N.Y.,(1990), Chapter 3; Cydectin® [moxidectin and derivatives]: G. T. Carteret al., J. Chem. Soc. Chem. Commun. (1987), pp. 402-404); EP 423 445-Al)"Doramectin --a potent novel endectocide" A. C. Goudie et al., Vet.Parasitol. 49 (1993), pp. 5-15).

Avermectins and their derivatives which may be particularly emphasizedare those of the general formula (I) ##STR1## in which the radicals R¹to R⁴ have the meaning indicated in Table 1 which follows and X can be asingle or double bond between the C₂₂ - and C₂₃ - positions (--C₂₂ R¹--X--C₂₃ R² --).

If there is a double bond, there are no substituents (R₁, R²) in theC₂₂ - and C₂₃ -positions.

                  TABLE 1                                                         ______________________________________                                        Macrocyclic lactone                                                                          --C.sub.22 R.sup.1 --X--C.sub.23 R.sup.2 --                                                  R.sup.3 R.sup.4                                 ______________________________________                                        Avermectin A.sub.1a                                                                          --CH═CH--                                                  sec-Bu                                                                                                    --Me                                                Avermectin A.sub.1b --CH═CH--                                            iso-Pr --Me                                                                    Avermectin A.sub.2a --CH.sub.2 --CHOH--                                      sec-Bu --Me                                                                    Avermectin A.sub.2b --CH.sub.2 --CHOH--                                      iso-Pr --Me                                                                    Avermectin B.sub.1a --CH═CH--                                            sec-Bu --H                                                                     Avermectin B.sub.1b --CH═CH--                                            iso-Pr --H                                                                     Avermectin B.sub.2a --CH.sub.2 --CHOH--                                      sec-Bu --H                                                                     Avermectin B.sub.2b --CH.sub.2 --CHOH--                                      iso-Pr --H                                                                     22,23-dihydroavermectin B.sub.1a --CH.sub.2 --CH.sub.2 --                    sec-Bu --H                                                                     22,23-dihydroavermectin B.sub.1b --CH.sub.2 --CH.sub.2 --                    iso-Pr --H                                                                     Doramectin --CH═CH-- --Chx --H                                          ______________________________________                                    

22,23-Dihydroavermectin B₁, is ivermectin;

sec-Bu=secondary butyl; iso-Pr=isopropyl; Chx=cyclohexyl; -Me=methyl

As a rule, the avermectins and 22,23-dihydroavermectins B₁ (ivermectin)of the general formula (I) are employed as mixtures. Of particularinterest in this connection is the product abamectin, which essentiallycontains the avermectins B₁, and their hydrogenation products, the22,23-dihydroavermectins B₁ (ivermectin).

The compounds of the macrocyclic lactones marked with "b" which in theC₂₅ -position have an iso-propyl radical, do not necessarily have to beseparated from the "a" compounds, which have a sec-butyl group in theC₂₅ - position. Generally the mixture of both substances, consistingof >80% sec-butyl derivative (B_(1a)) and <20% iso-propyl derivative(B_(1b)), is isolated, and can be used according to the invention.Additionally, in the stereoisomers the substituents in the C₁₃ - and C₂₃-positions can be arranged on the ring system both in the α- andβ-positions, i.e. are located above or below the plane of the molecule.In each case, all stereoisomers are taken into account according to theinvention.

The milbemycins may be mentioned particularly. The milbemycins have thesame macrolide ring structure as the avermectins or22,23-dihydroavermectins B₁ (ivermectin), but carry no substituents(i.e. missing oleandrose disaccharide fragment) in position 13 (R⁵=hydrogen).

As examples of milbemycins from the class of macrocyclic lactones, thecompounds having the general formula (II) may be mentioned ##STR2## inwhich the radicals R¹ to R⁴ have the meaning indicated in Table 2 whichfollows:

                                      TABLE 2                                     __________________________________________________________________________    Macrocyclic                                                                     lactone R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5                             __________________________________________________________________________    Milbemycin B41 D                                                                       --H --H                                                              iso-Pr                                                                                                       --H --H                                           - Nemadectin --H --OH                                                                                           --H --H                                     - Moxidectin --H ═N--O--Me                                                                                  --H --H                                  __________________________________________________________________________     iso-Pr = isopropyl                                                       

The active compounds which may be very particularly emphasized are

avermectin B_(1a) /B_(1b) (Abamectin),

22,23-dihydroavermectin B_(1a) /B_(1b) (ivernectin),

doramectin,

moxidectin.

The active compounds are present in the formulations according to theinvention in concentrations from 0.1 to 10% by weight, preferably from0.5 to 5% by weight, particularly preferably 1-2% by weight.

The castor oil employed in the formulations according to the inventionis known. It is used here in concentrations of 15 to 50% by weight.

The cosolvents employed in the formulations according to the inventionare known.

Suitable vegetable or synthetic fatty acid esters of polyhydric alcohols(oils) are fatty acid triglycerides, preferably fatty acid triglyceridesof medium chain length. Particularly suitable are neutral oils, such asneutral vegetable oils, and in particular fractionated coconut oils,such as are known and commercially available, for example, under thetrade name Miglyol, reference again being made to Lexikon derHilfsstoffe [Encyclopaedia of Auxiliaries], 3rd Edition, pages 808 to809, (1989) by Fiedler. These include, for example: Miglyol 810: this isa fractionated coconut oil which contains triglycerides of caprylic acidand capric acid and has a molecular weight of approximately 520. It hasa fatty acid composition with C₆ at most 2%, C₈ approximately 65 to 75%,C₁₀ approximately 25 to 35% and C₁₂ at most 2%, has an acid number ofapproximately 0.1, has a saponification number of approximately 340 to360 and has an iodine number of at most 1. Miglyol 812: this is afractionated coconut oil which contains triglycerides of caprylic acidand capric acid and has a molecular weight of approximately 520. It hasa fatty acid composition with C₆ at most 3%, C₈ approximately 50 to 65%,C₁₀ approximately 30 to 45% and C₁₂ at most 5%, has an acid number ofapproximately 0.1, has a saponification number of approximately 330 to345 and has an iodine number of at most 1. Miglyol 818: triglycerides ofcaprylic acid, capric acid and linolenic acid having a molecular weightof approximately 510. It has a fatty acid composition with C₆ at most3%, C₈ approximately 45 to 60%, C₁₀ approximately 25 to 40%, C₁₂approximately 2 to 5% and C₁₈ approximately 4 to 6, C₆ has an acidnumber of approximately 0.2, has a saponification number ofapproximately 315 to 335 and has an iodine number of at most 10. Captex355.sup.(1) : triglyceride of caprylic acid and capric acid. Thistriglyceride has a fatty acid content of caproic acid of approximately2%, of caprylic acid of approximately 55% and of capric acid ofapproximately 42%. It has an acid number of at most 0.1, has asaponification number of at most approximately 325 to 340 and has aniodine number of at most 0.5. Furthermore, also suitable aretriglycerides of caprylic acid and capric acid, such as the productsknown and commercially available under the trade name Myritol, for whichreference is made to Lexikon der Hilfsstoffe [Encyclopaedia ofAuxiliaries], 3rd Edition, page 834 (1989) by Fiedler. The productMyritol 813 belonging to these has an acid number of at most 1, has asaponification number of approximately 340 to 350 and has an iodinenumber of approximately 0.5.

The following are additionally suitable: monoglycerides, diglyceridesand mono/diglycerides, in particular esterification products of caprylicacid or capric acid with glycerol. Preferred products of this class are,for example, the products which contain monoglycerides and diglyceridesof caprylic acid/capric acid or consist essentially or virtuallythereof, and such products are commercially available under the tradename Imwitor, for which reference is made to Lexikon der Hilfsstoffe[Encyclopaedia of Auxiliaries], 3rd Edition, page 645 (1989) by Fiedler.A particularly suitable product from this class for use in thecompositions according to the invention is the product Imwitor 742,which is an esterification product of a mixture of approximately 60parts by weight (ppw) of caprylic acid and approximately 40 parts byweight (ppw) of capric acid with glycerol. Imwitor 742 is usually ayellowish crystalline mass, which is liquid at approximately 26° C. Ithas an acid number of at most 2, has an iodine number of at most 1, hasa saponification number of approximately 235 to 275, containsapproximately 40 to 50% of monoglycerides, has a content of freeglycerol of at most 2%, has a melting point of approximately 24 to 26°C., contains unsaponifiable constituents of at most 0.3% and has aperoxide number of at most 1.

Sorbitan fatty acid esters of the most different types known, such asare commercially available, for example, under the trade name Span, andthese include, for example, sorbitan monolauryl ester, sorbitanmonopalmityl ester, sorbitan monostearyl ester, sorbitan tristearylester, sorbitan monooleyl ester and sorbitan trioleyl ester, and forthese, reference is made, for example, to Lexikon der Hilfsstoffe[Encyclopaedia of Auxiliaries], 3rd Edition, pages 1139 to 1140 (1989)by Fiedler.

Pentaeryttritol fatty acid and polyalkylene glycol ethers, such aspentaerythritol dioleate, pentaerythritol distearate, pentaerythritolmonolaurate, pentaerythritol polyglycol ether and pentaerythritolmonostearate and also pentaerythritol fatty acid esters, for whichreference is made to Lexikon der Hilfsstoffe [Encyclopaedia ofAuxiliaries], 3rd Edition, pages 923 to 924 (1989) by Fiedler.

Monoglycerides, such as glycerol monooleate, glycerol monopalmitate andglycerol monostearate, such as are known and commercially available, forexample, under the trade names Myvatex, Myvaplex and Myverol, for whichreference is made to Lexikon der Hilfsstoffe [Encyclopaedia ofAuxiliaries], 3rd Edition, page 836 (1989) by Fiedler, and acetylated,for example monoacetylated and diacetylated, monoglycerides, such as areknown and commercially available, for example, under the trade nameMyvacet, for which reference is made to Lexikon der Hilfsstoffe[Encyclopaedia of Auxiliaries], 3rd Edition, page 835 (1989) by Fiedler.

Mono- and difatty acid esters of propylene glycol, such as propyleneglycol dicaprylate, propylene glycol dilaurate, propylene glycolhydroxystearate, propylene glycol isostearate, propylene glycol laurate,propylene glycol ricinoleate, propylene glycol stearate and the like,for which reference is made to Lexikon der Hilfsstoffe [Encyclopaedia ofAuxiliaries], 3rd Edition, pages 1013 ff. (1989) by Fiedler.Particularly preferred is propylene glycol caprylic acid capric aciddiester, which is known and commercially available under the trade nameMiglyol 840, for which reference is made to Lexikon der Hilfsstoffe[Encyclopaedia of Auxiliaries], 3rd Edition, page 809 (1989) by Fiedler.Miglyol 840 has a fatty acid content of C₆ of at most approximately 3per cent, C₈ approximately 65 to 80 per cent, C₁₀ approximately 10 to 30per cent and C₂ at most 3 per cent, and has an acid number of at most0.1, a saponification number of approximately 320 to 340 and an iodinenumber of at most 1.

Other suitable products of this class are Capmul MCT.sup.(1), Captex300.sup.(1), Captex 800.sup.(1), Neobee M5.sup.(2), Mazol 1400.sup.(3)and Imwitor.sup.(4)

.sup.(1) =Capital City Products, P.O. Box 569, Columbus, Ohio, USA

.sup.(2) =Stepan, PVO Dept., 100 West Hunter Ave., Maywood, N.J. 07607,USA

.sup.(3) =Mazer Chemicals, 3938 Porett Drive, Gurnee, Ill., USA

.sup.(4) =Huls AG, 14370 Marl, Germany

Other cosolvents are benzyl alcohol, which can simultaneously be used asa preservative, alcohols such as ethanol, glycol, glycerol, cycliccarbonates such as propylene carbonate. The cosolvents lie inconcentrations of 30-85% by weight.

Further additives are stabilizers such as butylhydroxyanisole (BHA),butyl-hydroxy-toluene (BHT) or propyl gallate of up to 1000 ppm intotal. Particularly suitable stabilizer combinations and concentrationsare, for example, 100 ppm of BHA or 100 ppm of BHA plus 150 ppm ofpropyl gallate or 200 ppm of BHA plus 100 ppm of propyl gallate.

The viscosity of the formulations according to the invention is between25 to 60 mPa.s (20° C.), preferably between 30 to 55 mPa.s (20° C.),particularly preferably between 35 and 51 mPa.s (20° C.).

The following examples illustrate the invention.

Note: ##EQU1## 1% m/v means, for example, 10 mg of active compound in 1ml of solution.

EXAMPLE 1

    __________________________________________________________________________    a) Miglyol ® 812                                                                     q.s. 100% v/v                                                                         b) Miglyol ® 812                                                                     q.s. 100% v/v                                      Castor oil 20% v/v  Caster oil 20% v/v                                        Benzyl alcohol 2% v/v  Benzyl alcohol 2% v/v                                  Ivermectin 1% m/v  Ivermectin 2% m/v                                          Density 0.954 g/ml  Density 0.956 g/ml                                        Viscosity 48 mPa.s at  Viscosity 48 mPa.s at                                   20° C.   20° C.                                                 95 mPa.s at   105 mPa.s at                                                    5° C.   5° C.                                               __________________________________________________________________________

EXAMPLE 2

    __________________________________________________________________________    a) Miglyol ® 812                                                                      q.s. 100% v/v                                                                        b) Miglyol ® 812                                                                      q.s. 100% v/v                                     Castor oil 20% v/v  Castor oil 20% v/v                                        Propylene carbonate 3% v/v  Propylene carbonate 3% v/v                        Benzyl alcohol 2% v/v  Benzyl alcohol 2% v/v                                  Ivermectin 1% m/v  Ivermectin 2% m/v                                          Density 0.962 g/ml  Density 0.964 g/ml                                        Viscosity 42 mPa.s at  Viscosity 44 mPa.s at                                   20° C.   20° C.                                                 91 mPa.s at   97 mPa.s at                                                     5° C.   5° C.                                               __________________________________________________________________________

EXAMPLE 3

    __________________________________________________________________________    a) Miglyol ® 812                                                                     q.s. 100% v/v                                                                         b) Miglyol ® 812                                                                     q.s. 100% v/v                                      Castor oil 20% v/v  Caster oil 20% v/v                                        Ivermectin 1% m/v  Ivermectin 2% m/v                                          Density 0.952 g/ml  Density 0.954 g/ml                                        Viscosity 51 mPa.s at  Viscosity 51 mPa.s at                                   20° C.   20° C.                                                 105 mPa.s at   117 mPa.s at                                                   5° C.   5° C.                                               __________________________________________________________________________

EXAMPLE 4

    __________________________________________________________________________    a) Miglyol ® 812                                                                     q.s. 100% v/v                                                                         b) Miglyol ® 812                                                                     q.s. 100% v/v                                      Castor oil 35% v/v  Caster oil 35% v/v                                        Ivermectin 1% m/v  Ivermectin 2% m/v                                          Density 0.939 g/ml  Density 0.941 g/ml                                        Viscosity 38 mPa.s at  Viscosity 42 mPa.s at                                   20° C.   20° C.                                                 75 mPa.s at   76 mPa.s at                                                     5° C.   5° C.                                               __________________________________________________________________________

EXAMPLE 5

    ______________________________________                                        a)  Ethyl oleate                                                                            q.s. 100% v/v                                                                            b)  Ethyl oleate                                                                          q.s. 100% v/v                               Castor Oil 45% v/v  Castor Oil 45% v/v                                        Ivermectin 1% m/v  Ivermectin 2% m/V                                          Density 0.916 g/ml  Density 0.918 g/ml                                        Viscosity 40 mPa.s at  Viscosity 49 mPa.s at                                   20° C.   20° C.                                                 91 mPa.s at   98 mPa.s at                                                     5° C.   5° C.                                               ______________________________________                                    

EXAMPLE 6

    __________________________________________________________________________    a) Miglyol ® 840                                                                      q.s. 100% v/v                                                                        b) Miglyol ® 840                                                                      q.s. 100% v/v                                     Castor oil 35% v/v  Castor oil 35% v/v                                        Propylene glycol 5% v/v  Propylene glycol 5% v/v                              Benzyl alcohol 5% v/v  Benzyl alcohol 5% v/v                                  Ivermectin 1% m/v  Ivermectin 2% m/v                                          Density 0.952 g/ml  Density 0.954 g/ml                                        Viscosity 36 mPa.s at  Viscosity 38 mPa.s at                                   20° C.   20° C.                                                 76 mPa.s at   81 mPa.s at                                                     5° C.   5° C.                                               __________________________________________________________________________

EXAMPLE 7

    ______________________________________                                        a)       Ethyl oleate    q.s. 100% v/v                                           Castor oil 40% v/v                                                            Propylene glycol 5% v/v                                                       Benzyl alcohol 5% v/v                                                         Ivermectin 1% m/v                                                             Density 0.926 g/ml                                                            Viscosity 34 mPa.s at 20° C.                                            70 mPa.s at 5° C.                                                  ______________________________________                                    

EXAMPLE 8

    ______________________________________                                        a)         Miglyol ® 840                                                                           q.s. 100% v/v                                           Castor oil 35% v/v                                                            Benzyl alcohol 20% v/v                                                        Ivermectin 1% m/v                                                             Density 0.965 g/ml                                                            Viscosity 28 mPa.s at 20° C.                                            56 mPa.s at 5° C.                                                  ______________________________________                                    

EXAMPLE 9

    ______________________________________                                        a)       Miglyol ® 840                                                                             q.s. 100% v/v                                           Castor Oil 35% v/v                                                            Propylene carbonate 10% v/v                                                   Benzyl alcohol 5% v/v                                                         Ivermectin 1% m/v                                                             Density 0.975 g/ml                                                            Viscosity 27 mPa.s at 20° C.                                            53 mPa.s at 5° C.                                                  ______________________________________                                    

EXAMPLE 10

    ______________________________________                                        a)         Imwitor ® 408                                                                           q.s. 100% v/v                                           Castor oil 30% v/v                                                            Ivermectin 1% m/v                                                             Density 0.953 g/ml                                                            Viscosity 30 mPa.s at 20° C.                                            66 mPa.s at 5° C.                                                  ______________________________________                                    

Imwitor® is a trade name of Huls AG. Imwitor® 408 is 1,2-propanediolmono-dicaprylate (INCI (CTFA) name). According to provisional productinformation, Imwitor® 408 contains about 10% free propylene glycol andabout 50% monoglycerides. It has a high dissolving power for Ivermectin(>20% m/v).

General Preparation Procedure for Examples 1 to 10 as Sterile Solutionsfor Injection:

The formulation auxiliaries are weighed into a stainless steel containerand homogenized with stirring. The Ivermectin is introduced with furtherstirring. The mixture is warmed to 40 to 50° C. in order to acceleratethe dissolution of the active compound (if possible with nitrogenaeration). After complete dissolution, the mixture is thensterile-filtered at the same temperature through a 0.22 μm filter (as arule a 0.45 μm or 1 μm filter is preinserted). Aseptic dispensing intobrown glass bottles follows.

The formulations prepared in this way are outstandingly tolerable whenused in cattle. They are additionally stable on storage at temperaturesbetween 4° C. and 60° C. over at least 6 weeks.

We claim:
 1. Injection formulations of avermectins or milbemycinscomprising a castor oil vehicle, characterized in that they have thefollowing composition:1. avermectins or milbemycins 0.1 to 10% byweight;
 2. castor oil vehicle 15 to 50% by weight;
 3. one or moreco-solvents from the series consisting of vegetable or synthetic fattyacid esters of mono- or polyhydric alcohols, aliphatic or aromaticalcohols, cyclic carbonates in concentrations of 30 to 85% by weight; 4.optionally, further auxiliaries.
 2. Formulations according to claim 1 ofthe following composition:0.1 to 10% m/v of an avermectin or milbemycinin a solvent mixture consisting of 15 to 50% v/v of castor oil, and 30to 85% v/v of medium-chain triglyceride and/or propylene glycoloctanoate/decanoate and/or ethyl oleate and 0 to 30% v/v of one or of amixture of the solvents benzyl alcohol, propylene glycol or propylenecarbonate, and optionally up to 1000 ppm of stabilizers.
 3. Formulationsaccording to claim 1 of the following composition:20 to 45% v/v ofcastor oil, 45 to 80% v/v of medium-chain triglycerides or propyleneglycol octanoate/decanoate or ethyl oleate and 0 to 20% v/v of benzylalcohol, 0 to 10% v/v of propylene glycol or propylene carbonate, andoptionally up to 500 ppm of stabilizers.
 4. Process for the preparationof the formulations according to claim 1, characterized by the step ofmixing the ivermectins or milbemycins with castor oil, followed byadding the cosolvents or the step of dissolving the avermectins ormilbemycins in a mixture of castor oil and the cosolvents.
 5. A processfor administering to animals the formulations of claim 1 comprising ginjecting the animals with the formulations.